WO2005058914A1

WO2005058914A1 - Crystal of oxacephem

Info

Publication number: WO2005058914A1
Application number: PCT/JP2005/002607
Authority: WO
Inventors: Masaaki Uenaka; Koichi Noguchi
Original assignee: Shionogi & Co., Ltd.
Priority date: 2004-02-20
Filing date: 2005-02-18
Publication date: 2005-06-30
Also published as: KR100832757B1; TWI338008B; CN101440098A; CN1922191A; TW200533672A; KR20060120253A; CN100509819C; JP4530287B2; CN101440098B; JPWO2005058914A1

Abstract

Provided are a hydrate of flomoxef or a solvate of flomoxef with methyl acetate, and crystals of these. They are advantageous from an environmental standpoint and for formulation into pharmaceutical preparations, etc. flomoxef

Description

Oxacephem crystal

Technical field

[0001] The present invention relates to the formation of oxacephem useful as an antibacterial agent.

Background art

[0002] Formula:

Is useful as an Oxasefm antimicrobial agent. A lyophilized preparation containing the Na salt is commercially available as an injection (trade name: Flumarin, Shionogi & Co., Ltd.). The freeze-dried preparation is produced by using flomoxef as a main raw material and blending sodium chloride and a stabilizer (see Patent Document 1).

Flomoxef crystals are also known.For example, the corresponding protected carboxylic acid at the 4-position is treated with methylene chloride and alcohol, with a Lewis acid (TiCl or A: i) and then with ethyl acetate.

4 3

The force has also crystallized (see Patent Document 2, Example 3). Alternatively, the intermediate in which the carboxylic acid at the 4-position and the hydroxyl group at the 3-position end are protected with a Lewis acid (SnCl 2) in the same manner as in the case of ethanol, and then the methylene chloride and acetone are crystallized. Is known (non-

Four

Patent Document 1). These crystal forms are not described in detail. However, according to the additional examination by the present inventors, methylene chloride-containing crystals can be obtained by the method of the literature.

[0003] Patent Document 1: JP-A-60-45514

Patent Document 2: JP-A-59-139385

Non-Patent Document 1: The Journal of Antibiotics (Apr. P466-476, 1985)

Disclosure of the invention

Problems the invention is trying to solve [0004] From the methylene chloride-containing crystals of flomoxef, it is not easy to degas the methylene chloride by an ordinary drying method. Until now, as a formulation method in actual production, as described in Patent Document 1, freeze-drying has been carried out also as sterilization to obtain a sodium salt containing no methylene chloride. However, the freeze-drying method generally requires a high production cost and a heavy burden in terms of equipment maintenance. Therefore, recently, it has been desired to employ a method other than the freeze-drying method, if possible, as a more efficient industrial method for producing a sterile injectable preparation. Flomoxef, which does not contain methylene chloride, can itself be used as a pharmaceutically active ingredient. Therefore, new crystals that do not contain methylene chloride and are more advantageous for the formulation of Flomoxef have been required.

Means for solving the problem

The present inventors have conducted intensive studies in view of the above problems, and as a result, have found a novel solvate-containing crystal of flomoxef, and have completed the present invention described below.

(1 set:

[Formula 2]

A hydrate or hydrate crystal of the compound (I) represented by

(2) The hydrate or hydrate crystal according to the above 1, which is a monohydrate.

(3) In the powder X-ray diffraction pattern, there are main peaks at d-8.31, 7.00, 6.11, 5.43, 4.47, 4.35, 4.19, 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (angstrom). 3. The hydrate crystal according to 1 or 2 above.

Equation (4):

[Formula 3]

Or a methyl acetate solvate of the compound (I) represented by the formula:

(5) The methyl acetate solvate or the methyl acetate solvate according to the above-mentioned 4, which is 0.5 methyl acetate solvate.

(6) In the powder X-ray diffraction pattern, the above has a main peak at the plane spacing d = 10.42, 6.32, 4.96, 4.62, 4.56, 4.36, 4.23, 3.97, 3.93, 3.79, 3.47, 2.79 (unit: angstrom). 4. The crystalline methyl acetate acetate according to 4 or 5.

The invention's effect

[0007] The novel solvate of flomoxef of the present invention is preferably a crystal, which is advantageous for formulation with improved stability and handleability. In particular, hydrate crystals do not contain organic solvents such as methylene chloride, so they may be directly formulated into injections by the powder filling method. Methyl acetate hydrate crystals are more advantageous in terms of safety and environmental aspects than crystals containing methylene chloride, and can produce flomoxef industrially and efficiently. That is, these crystals can be used as a pharmaceutically active ingredient or an intermediate thereof. BEST MODE FOR CARRYING OUT THE INVENTION

[0008] Each solvate of the present invention and its crystal will be described.

(1) hydrate

The hydrate of flomoxef preferably contains one molecule of water per one molecule of flomoxef. The hydrate is preferably crystalline. Preferably, the crystal mainly has a face spacing d = 8.31, 7.00, 6.11, 5.43, 4.47, 4.35, 4.19, 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (unit: angstrom) in the powder X-ray diffraction pattern. It has a peak, and more specifically, the putter shown in Table 1 below and FIG. 1 is shown. (X-ray diffraction measurement conditions: tube CuKa line, tube voltage 40 Kv, tube current 30 mA, dsin θ = η λ (η is an integer, θ is the diffraction angle))

In the present specification, the d-spacing is, for convenience, the main peak among the X-ray peaks, and the strength of the relative intensity is selected. The force The crystal structure is necessarily limited only by these values. is not. That is, peaks other than these may be included. In general, when a crystal is measured by X-ray analysis, its peak may cause some measurement error depending on the measuring instrument, the measuring conditions, the presence of the attached solvent, and the like. Therefore, some errors should be taken into account in the identification of the crystal structure. All crystals characterized by a pattern are within the scope of the present invention.

The above hydrate can be obtained, for example, by adding flomoxef or its methylene chloride hydrate obtained according to the method described in JP-A-59-139385 or The Journal of Antibiotics (Apr. P466-476, 1985) in a small amount of a soluble solvent. After dissolving at room temperature or warming (preferably about 20-40 ° C), pour a larger amount of water than the soluble solvent at room temperature or under ice-cooling, and then add 0 ° C-about room temperature, preferably about 5- It is obtained by stirring or standing at 25 ° C for several hours and one day. The amount of the soluble solvent to be used is preferably 0.1 to 10 mL, preferably 0.5 to 5 mL, more preferably 13 to 13 mL per 1 g of flomoxef. The amount of water used is preferably 1 to 100 mL, preferably 5 to 50 mL, more preferably 10 to 30 mL per lg of Flomoxef.

Examples of the soluble solvent include alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol, and ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diethylene dimethyl ether. , Acetone, methyl ethyl ketone, ketones such as methyl isobutyl ketone, methyl format, ethyl format, propyl format, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl Esters such as propionate, organic halo such as methylene chloride, chloroform, tetrachloride carbon, 1,2-dichloroethane, trichloroethane, cyclobenzene, dichlorobenzene, etc. Ni 匕炭 hydrogen acids, Asetonitoriru, propionic - tolyl etc. - tolyl ethers, dimethylformamide, dimethyl sulfoxide, dimethyl § Seth amide, N- methylpyrrolidone, quinoline, pyridine, and the like can be used Toryechiruamin. These solvents may be used alone or in combination of two or more.

The crystals thus obtained are then separated from the solvent by conventional separation means (eg, filtration, centrifugation, etc.) and subjected to conventional purification means (eg, washing, air drying, drying under reduced pressure). Can be isolated.

In addition, the above hydrate is obtained by heating and dissolving an extraction residue containing Flomoxef or an organic solvate thereof in water, which is also capable of obtaining a reaction liquid obtained by deprotecting the Flomoxef intermediate. For several hours and several days.

(2) Methyl acetate solvate The methyl acetate solvate of flomoxef preferably contains 0.5 to 1.0, more preferably 0.5, methyl acetate molecules per one molecule of flomoxef. The methyl acetate solvate is preferably crystalline. The crystal preferably has a main peak in the powder X-ray diffraction pattern at an interplanar spacing d = 10.42, 6.32, 4.96, 4.62, 4.56, 4.36, 4.23, 3.97, 3.93, 3.79, 3.47, 2.79 (unit: angstrom). More specifically, the putter shown in Table 3 or FIG. 2 is shown below.

The methyl acetate hydrate is obtained, for example, as follows. After dissolving Flomoxef or its methylene chloride hydrate in methyl acetate under heating (preferably at about 20-40 ° C), the solvent is distilled off. The residue is heated and dissolved in methyl acetate (preferably about 20-40 ° C), and then stirred at 0 ° C-room temperature for several hours and several days. It is obtained by filtering the precipitated crystals, preferably washing with cold methyl acetate, and air-drying. The amount of methyl acetate used in the first and second times is preferably 0.1 to 20 mL, preferably 0.5 to 15 mL, more preferably 110 to 10 mL, per 1 g of flomoxef. The amount of water used is preferably 1 to 100 mL, preferably 5 to 50 mL, and more preferably 10 to 30 mL, per 1 g of Flomoxef.

The methyl acetate hydrate can also be obtained in the same manner as described above, using the extraction residue of the reaction solution obtained by deprotecting the intermediate of flomoxef as a raw material.

The above hydrate or methyl acetate solvate can be converted to another solvate or crystal if desired. It can also be formulated alone or, if desired, together with a pH adjuster, stabilizer and the like by freeze-drying method, powder filling method and the like. In particular, hydrates are advantageous for formulation, since they can be preferably formulated by the powder filling method.

Reference example 1

[Formula 4]

(Where Me = methyl; BH = benzhydryl)

Non-Patent Document 1 (The Journal of Antibiotics (Apr. P466-476, 1985)) describes an intermediate of mouth moxef (benzhydryl at the 4-position of flomoxef, hydroxy on 3-position tetrazole methylbenzyloxycarbo) (405 mg), methylene chloride (2.5 ml) and tromethane (0.5 ml) were cooled to 30 ° C and contained ethanol (0.11 ml) and SnCl (0.17 ml). Mix the methylene chloride (2 ml) solution and stir for 3 hours and a half.

Four

And gradually heated to 10 ° C. The reaction mixture was poured into a mixture of 1N hydrochloric acid, ethyl acetate and methyl ethyl ketone, and the separated organic layer was mixed with an aqueous solution of sodium hydrogen carbonate, the aqueous layer was acidified with concentrated hydrochloric acid, and ethyl acetate and methyl ethyl were added. Extracted with a mixture of ketones. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and dried under reduced pressure to obtain a foamy reaction extract residue containing methylene chloride hydrate of flomoxef.

Example 1

After lOOOOmg of the reaction extraction residue obtained in Reference Example 1 was dissolved by heating in 20mL of water, the mixture was stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 10 mL of cold water. Air drying and drying under reduced pressure (conditions: 50 Pa, 5 to 10 hours) gave 803 mg (77%) of flomoxef monohydrate crystals.

IR (Nujol): 3539, 3198, 2924, 2854, 1776, 1711, 1685, 1645, 1534, 1450, 1387, 1267, 1130, 1062, 1039, 997, 861, 665 cm— ¹

^J H NMR (DMSO-d6); δ 3.36 (3Η, s), 3.59 (1Η, d, J = 15.3 Hz), 3.66 (1H, d, J = 15.3 Hz), 3.73 (2H, t, J = 5.1 Hz), 4.18 (1H, d, J = 13.5 Hz), 4.23 (1H, d, J = 13.5 Hz), 4.31 (2H, t, J = 5.1 Hz), 4.52 (2H, s), 5.06 (2H, brs), 7.30 (1H, t, J = 56.4 Hz), 9.25 (1H, s)

Elemental analysis: C H N O F S -H O

15 18 6 7 2 2 2

Theoretical value: C35.02, H3.92, N16.33, F7.39, S12.46

Obtained values: C35.05, H3.93, N16.39, F7.22, S12.32

Water content

Theoretical value (monohydrate): 3.50%

Karl Fischer moisture meter (KF) measurement: 3.52%

Melting point: 94 ° C The X-ray powder diffraction pattern is shown in Table 1 and FIG.

[table 1]

2 Θ d value Relative strength

10.64 8.30 13

12.64 7.00 10

14.48 6.11 14

16.30 5.43 12

16.56 5.34 4

19.04 4.66 6

19.86 4.47 24

20.40 4.35 17

21.18 4.19 13

21.38 4.15 23

22.48 3.95 13

23.30 3.81 13

23.88 3.72 5

24.62 3.61 5

25.46 3.50 13

25.64 3.47 8

26.86 3.31 20

27.24 3.27 8

28.36 3.14 5

29.62 3.01 6

30.20 2.96 13

31.24 2.86 7

32.36 2.76 5

33.50 2.67 6

33.66 2.66 7

33.84 2.65 6

35.04 2.56 5

35.78 2.51 5

36.20 2.48 6 Example 2

The reaction extraction residue obtained in Reference Example 1 was dissolved in a soluble solvent at room temperature or with heating under the conditions shown in Table 2 below, and water was added at room temperature or with ice cooling. The mixture was stirred or allowed to stand at 5-25 ° C for several hours a day. All the obtained crystals contained no organic solvent by NMR, and were confirmed to be monohydrate by elemental analysis. Also, the same powder X-ray diffraction pattern as in Example 1 was shown.

[Table 2]

Example 3

The reaction extraction residue lOOOOmg obtained in Reference Example 1 was dissolved by heating in 5 mL of methyl acetate, and the solvent was distilled off. The residue was heated and dissolved in 2 mL of methyl acetate, and then stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 2 mL of cold methyl acetate. After air drying, 784 mg (82%) of crystals of 0.5 methyl acetate hydrate were obtained.

IR (Nujol): 3493, 3249, 3041, 2925, 2853, 1765, 1737, 1711, 1668, 1643, 1543, 1457, 1441, 1420, 1392, 1376, 1248, 1231, 1080, 1062, 1042, 1030, 805 , 751 1H NMR (DMSO-d6); δ 3.36 (3Η, s), 3.59 (IH, d, J = 15.3 Hz), 3.66 (IH, d, J = 15.3 Hz), 3.73 (2H, t, J = 5.1 Hz), 4.18 (IH, d, J = 13.5 Hz), 4.23 (IH, d, J = 13.5 Hz), 4.31 (2H, t, J = 5.1 Hz), 4.51 (2H, s), 5.06 (2H , brs), 7.30 (IH, t, J = 56.4 Hz) and 9.25 (IH, s) NMR showed peaks of methyl acetate 0.5 molecule 1.98 (3H, s) and 3.55 (3H, s).

Elemental analysis: C H N 0 F S · 1/2 AcOMe

15 18 6 7 2 2

Theoretical value: C37.15, H3.97, N15.75, F7.12, S12.02

Obtained values: C36.96, H3.92, N15.55, F6.98, S11.96

Melting point: 78 ° C

The powder X-ray diffraction pattern is shown in Table 3 and FIG. [Table 3]

2 θ d value Relative intensity

8.48 10.42 38

11.34 7.80 6

11.70 7.56 5

14.00 6.32 10

16.94 5.23 7

17.86 4.96 15

19.20 4.62 14

19.46 4.56 23

20.00 4.44 8

20.36 4.36 33

21.00 4.23 17

22.36 3.97 15

22.62 3.93 12

23.48 3.79 12

24.50 3.63 6

25.66 3.47 18

26.78 3.32 7

27.02 3.30 9

27.42 3.25 6

27.82 3.20 9

30.80 2.90 9

31.70 2.82 8

32.04 2.79 10

Example 4

The reaction extraction residue lOOOOmg obtained in Reference Example 1 was dissolved by heating in 5 mL of methyl acetate, and the solvent was distilled off. The residue was heated and dissolved in 2 mL of methyl acetate, and then stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 2 mL of cold methyl acetate. Air dried to obtain 838 mg (78%) of crystals of 0.5 methyl acetate hydrate as in Example 3.

Brief Description of Drawings

FIG. 1 shows a powder X-ray diffraction pattern of a monohydrate crystal of flomoxef obtained in Example 1.

2 shows a powder X-ray diffraction pattern of 0.5-methyl acetate solvate of flomoxef obtained in Example 3. FIG.

Claims

Claim [1] Formula:

[Chemical 1]

A hydrate or hydrate crystal of the compound (I) represented by

[2] The hydrate or hydrate crystal according to claim 1, which is a monohydrate.

[3] In the powder X-ray diffraction pattern, the spacing d = 8.31, 7.00, 6.11, 5.43, 4.47, 4.35,

3. The hydrate crystal according to claim 1, which has a main peak at 4.19, 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (unit: angstrom).

[4] Formula:

[Formula 2]

Or a methyl acetate solvate of the compound (I) represented by the formula:

5.Methyl acetate solvate or methyl acetate solvate according to claim 4, which is 0.5 methyl acetate solvate o

Claim 4 having a main peak at a plane spacing d = 10.42, 6.32, 4.96, 4.62, 4.56, 4.36, 4.23, 3.97, 3.93, 3.79, 3.47, 2.79 (unit: angstrom) in the powder X-ray diffraction pattern or 5. A methyl acetate hydrate crystal according to 5.